PROJECT SUMMARY: Cardiogenic shock develops in 7-10% of patients with acute Myocardial Infarction (MI), and has a high mortality ranging 50-70%. Short-term Left Ventricular (LV) unloading is a new concept that became a reality with the recent emergence of powerful percutaneous Left Ventricular Assist Devices (pLVAD)s, which offers significant promise for improving the outcomes of the patients with cardiogenic shock. Several clinical and pre- clinical studies demonstrated clear improvement in hemodynamics using these devices, however no clinical studies have so far shown improvement in 30-day clinical outcome. Current data suggest that pLVADs improve hemodynamics and very acute clinical outcome (~24hr), but the functional recovery of injured heart during LV support is often not sufficient to maintain the hemodynamics after the devices are removed, resulting in only slowing of the death. Large amount of research focus on short-term LV unloading is on the acute changes in hemodynamics and when, how, and to whom we introduce these devices. In contrast, little is studied on how we exit from these device therapies. Here, in order to maximize the benefit of pLVADs use for cardiogenic shock, we propose to study key elements that may influence functional recovery of native heart after LV unloading with pLVADs. Specifically, we propose to study 1) impact of LV re-loading, 2) impact of cardiac molecular alterations associated with LV unloading, and 3) adjunctive approach to boost cardiac functional recovery. Our central hypothesis is that initiation of LV unloading as well as re-loading negatively influence cardiac function, and additional therapy is required to improve the clinical outcomes of patients with cardiogenic shock treated with pLVADs. To test our central hypothesis we propose below Specific Aims. Specific Aim 1. Define the impact of LV re-loading Specific Aim 2. Define the impact of LV unloading on post-translational modification in key cardiac proteins Specific Aim 3. Use gene therapy to promote myocardial recovery Our study will increase the understanding of molecular changes in the heart after LV unloading and re- loading. As we foresee increase in pLVADs use for patients with cardiogenic shock, identifying the potential harm and developing ways to improve current low survival with short-term LV unloading has a significant clinical impact.